Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model.

ABSTRACT: The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA₁ interacts with TRIM21, and α-GA₁ treatment reduced GA levels, increased GA turnover, and decreased RAN toxicity and co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA₁ reduced GA as well as GP and GR proteins, improved behavioral deficits, decreased neuroinflammation and neurodegener

SUBMITTER: Nguyen L 

PROVIDER: S-EPMC7391607 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature